The pivotal role of endotoxin adult respiratory distress resulting from gram negative infection is well known. However, pulmonary effects of massive daily inhalation of endotoxin in a wide variety of occupational environments have, until recently, been largely unknown and neglected. There are presently important inconsistencies between epidemiologic, experimental human and animal studies of inhaled endotoxin. These may arise from inability to measure the total content and physical state of endotoxins in aerosol samples and from different biological behavior of soluble and cell membrane bound endotoxin. We have reported progress toward an assay for endotoxin which may resolve these difficulties. The goal of this work is to examine the importance of inhaled endotoxin to the pathogenesis of certain lung diseases and to the respiratory health of heavily exposed populations. We hope to contribute to a sound scientific basis for a decision on whether to regulate airborne endotoxin. First, we will develop a new Limulus amebocyte lysate (LAL) based assay for total, membrane bound and soluble endotoxin content of aerosol samples. We will employ the new assay to measure and characterize endotoxin exposure from cotton dust and machining fluids and indoor air. We will determine if the pulmonary toxicities of cell membrane-bound and soluble endotoxins differ in an animal model. To gauge the importance and characterize the role of endotoxin versus other potential toxins in cotton dust, we will expose endotoxin sensitive and tolerant animals and contrast their inflammatory and ventilatory responses. Finally, we will seek exposure-response relationships between endotoxin in work place air and pulmonary effects among 1850 machining fluid exposed auto workers and 250 cotton mill workers. For this work we will employ the new assay for endotoxin and experimentally derived estimates of the relevant exposure parameters. We expect that personal air samples, historical industrial hygiene data and complete mortality as well as current respiratory health data for the machining fluid workers will allow an unusual opportunity to observe a relationship of endotoxin to pulmonary morbidity and to mortality from chronic pulmonary disease and lung cancer, if a relationship exists. The candidate is ideally suited for the award because of his unique combination of training in epidemiology, biostatistics, biochemistry, experimental pathology and occupational medicine, his demonstrated research interest and his commitment to a career as an independent investigator of occupational lung disease. The environment is an established laboratory and an occupational health program with proven success in training individuals in respiratory biology and occupational epidemiology.